Yellon D

The "metabolic cocktail" comprising glucose-insulin-potassium administrated at reperfusion reduces infarct size in the in vivo rat heart. We propose that insulin is the major component mediating this protection and acts via Akt prosurvival signaling. This hypothesis was studied in isolated perfused rat hearts (measuring infarct size to area of risk [%]) subjected to 35 minutes regional myocardial ischemia and 2 hours reperfusion. Insulin administered at the onset of reperfusion attenuated infarct size by >/=45% versus control hearts (P<0...

Apoptosis contributes to myocardial cell death during ischemia and reperfusion, especially during reperfusion. Growth factor "survival" signaling attenuates apoptosis. We therefore examined the effects of transforming growth factor-beta1 (TGF-beta1) on reperfusion injury and assessed the role of p42/p44 MAPK signaling in TGF-beta1-induced protection. Rat ventricular myocytes were subjected to hypoxia and reoxygenation. TGF-beta1 (0.2 ng/ml) was applied to cells during reoxygenation and the extent of apoptosis was determined by TUNEL and annexin V binding assays...

Nitric oxide (NO) is implicated in triggering and mediating delayed preconditioning. However, the role of NO and endothelial nitric oxide synthase (eNOS) in early ischaemic preconditioning is controversial. To investigate the role of eNOS in this paradigm further, the response of hearts isolated from either eNOS knockout (KO) or eNOS wild type (WT) mice to various ischaemic-preconditioning stimuli were studied. To determine whether eNOS is pivotal to early ischaemic preconditioning, hearts from both groups were subjected to a robust ischaemic-preconditioning stimulus consisting of four cycles of 5 min ischaemia and reperfusion (4PC) prior to an injurious ischaemia/reperfusion insult...

Pharmacological uncoupling of mitochondrial oxidation from phosphorylation promotes preconditioning-like cardioprotection in the isolated rat heart. We hypothesized that modest mitochondrial uncoupling may be a critical cellular event in orchestrating preconditioning. Human-derived Girardi cells and murine C2C12 skeletal myotubes were preconditioned using simulated ischemia, adenosine, and diazoxide. Cell viability after 6 hours of simulated ischemia was measured using lactate dehydrogenase release and propidium iodide uptake...

Ischemic preconditioning (IP) reduces infarct size in young animals; however, its impact on aging is underinvestigated. The effect of variations in IP stimuli was studied in young, middle-aged, and aged rat hearts. Isolated hearts underwent 35 min of regional ischemia and 120 min of reperfusion. Hearts with IP were subjected to either one ischemia-reperfusion cycle (5 min of ischemia and 5 min of reperfusion per cycle) or three successive cycles before 35 min of regional ischemia. Additional studies investigated the effects of pharmacological preconditioning in aged hearts using the adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine, the protein kinase C analog 1,2-dioctanoyl-sn-glycerol, and the mitochondrial ATP-sensitive potassium (K(ATP))-channel opener diazoxide...

BACKGROUND: Recent concern regarding interference with facial skeletal growth and the risk of complications after endoscopic sinus surgery (ESS) has led to interest in exploring other treatment options for the management of chronic sinusitis in children. OBJECTIVE: To present the use of a stepwise protocol that includes intravenous (IV) antibiotic therapy as a therapeutic alternative to pediatric ESS. DESIGN: Retrospective analysis of pediatric patients with chronic sinusitis treated from January 1, 1993, to July 1, 1998, with a stepwise protocol that includes the use of IV antibiotics...

OBJECTIVES: The mechanism by which the mitochondrial K(ATP) channel openers confer protection against ischemia/reperfusion injury is debated. Evidence suggests that rather than solely being an end effector, opening of these channels may act by a trigger mechanism. We examined the effects of the mitochondrial K(ATP) channel opener, diazoxide on parameters of mitochondrial function with specific reference to reactive oxygen species (ROS) generation in a human atrial derived cell line model of simulated ischemia/reperfusion (LSI/R)...

Bradykinin is an important endogenous mediator exerting acute protective effects in the ischemic myocardium. The aims of this study were to investigate whether exogenously administered bradykinin could evoke delayed myocardial protection and to determine whether any protection observed might be dependent on nitric oxide (NO) generation. Conscious rats received bradykinin (40 microg/kg iv) or saline, preceded 15-20 min earlier by the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg ip) or saline...

Pineal melatonin secretion has been reported to commonly decrease with aging, whereas intra-abdominal adiposity, plasma insulin and plasma leptin levels tend to increase. We recently demonstrated that daily melatonin administration starting at middle age suppressed male rat intra-abdominal fat, plasma leptin and plasma insulin to youthful levels, suggesting that aging-related changes in pineal melatonin secretion and in energy regulation may be functionally related. Accordingly, we have now investigated the effects of daily melatonin treatment on energy regulation in young versus middle-aged male Sprague Dawley rats...

Transient adenosine A1 receptor (A1R) activation induces a second window or delayed preconditioning against myocardial infarction 24-72 h later. Early generation of nitric oxide and delayed induction of nitric oxide synthase have been implicated in mediating delayed cardioprotection after ischemic preconditioning in rabbits. Recent evidence indicates that some of the regulatory roles of adenosine in cardiac tissue may be mediated by A1R-induced generation of nitric oxide. This study examined the role of nitric oxide in the mediation of A1R-induced delayed preconditioning against infarction...

OBJECTIVE: The cytokine cardiotrophin-1 (CT-1) has previously been shown to protect cultured cardiocytes from cell death induced by serum removal or hypoxia when administered prior to the damaging stimulus. We wished to test whether a similar protective effect could be observed if CT-1 was added after the ischaemic period and to investigate the signalling pathways involved in the protective effect when CT-1 is given prior to or after ischaemia. METHODS: We therefore examined the protective effect of CT-1 in cultured rat cardiocytes exposed to simulated ischaemia followed by reoxygenation when CT-1 was administered either prior to simulated ischaemia or at reoxygenation...

BACKGROUND: Cardiac harvest teams are usually committed to immediately transfer the explanted donor heart into its cold storage solution. We tested the opposite hypothesis that a brief prestorage episode of heat-enhanced ischemic preconditioning could be protective. METHODS: Fifty-three isolated isovolumic rat hearts underwent 4 hours of cold (4 degrees C) storage in the Celsior preservation solution and 2 hours of reperfusion. Control hearts were immediately immersed after arrest...

BACKGROUND: The sulfonylurea glibenclamide (Glib) abolishes the cardioprotective effect of ischemic preconditioning (IP), presumably by inhibiting mitochondrial K(ATP) channel opening in myocytes. Glimepiride (Glim) is a new sulfonylurea reported to affect nonpancreatic K(ATP) channels less than does Glib. We examined the effects of Glim on IP and on the protection afforded by diazoxide (Diaz), an opener of mitochondrial K(ATP) channels. METHODS AND RESULTS: Rat hearts were Langendorff-perfused, subjected to 35 minutes of regional ischemia and 120 minutes of reperfusion, and assigned to 1 of the following treatment groups: (1) control; (2) IP of 2x 5 minutes each of global ischemia before lethal ischemia; or pretreatment with (3) 30 micromol/L Diaz, (4) 10 micromol/L Glim, (5) 10 micromol/L Glib, (6) IP+Glim, (7) IP+Glib, (8) Diaz+Glim, or (9) Diaz+Glib...

OBJECTIVES: We assessed the effect of angiotensin-converting enzyme (ACE) inhibition in combination with a subthreshold preconditioning (PC) stimulus to elicit delayed preconditioning against infarction in pig myocardium. BACKGROUND: Bradykinin triggers early PC. Angiotensin-converting enzyme inhibitors increase local bradykinin levels via inhibition of kinin breakdown and have been shown in experimental studies to augment early protection afforded by PC. A role for bradykinin in eliciting delayed PC has not so far been identified...

OBJECTIVE: Management of chronic aspiration of saliva is a challenge to clinicians. The purpose of this report is to review the clinical course of 3 patients with tracheotomy who we have followed for at least 1 year and who have received constant positive airway pressure (CPAP) as a primary treatment for ongoing aspiration of saliva. METHODS: Retrospective chart review. RESULTS: We present here 3 patients with chronic congestion and persistent hypoxemia in whom a diagnosis of chronic aspiration of saliva was established by use of radionuclide salivagram...

Adenosine A1 receptor agonists given prior to myocardial ischemia limit ischemic injury in several species. However, the ability of adenosine receptor agonists to limit infarct size when given at reperfusion has proved controversial. We designed a three-center experimental study using a blinded, randomized treatment protocol to test the hypothesis that adenosine A1 receptor activation during early reperfusion can attenuate lethal reperfusion injury, thereby reducing infarct size. Sixty anesthetized rabbits (20 in each laboratory) underwent 30 minutes coronary artery occlusion followed by 120 minutes reperfusion...

There is debate concerning the involvement of p38 mitogen activated protein kinase (MAPK) in the mediation of ischaemic preconditioning. Pharmacological inhibition of p38 MAPK with SB203580 has been reported to block preconditioning in some studies but not in others. We hypothesised that this divergence could be due to differences in the timing of inhibitor administration. Isolated rat hearts were perfused in the Langendorff mode and subjected to 35 min regional ischaemia followed by 120 min reperfusion. Hearts were then double stained with Evans' blue and triphenyltetrazolium chloride to determine risk (R) and infarct zones (I), expressed as I/R% ratios...

OBJECTIVE: To determine whether exercise is capable of protecting the myocardium from experimental infarction and to explore the involvement of protein kinase C, a key signalling protein, in the development of any protection observed. METHODS: Rats were exercised on a treadmill for 30 minutes at 23-27 m/min. Sham treated animals were placed on the stationary treadmill but not exercised. Twenty four hours later, hearts were Langendorff perfused and subjected to 35 minute left main coronary artery occlusion followed by 120 minute reperfusion...

OBJECTIVES: The objective of this study was to examine whether the delta (delta) opioid receptor isoform is expressed in the human heart and whether this receptor improves contractile function after hypoxic/reoxygenation injury. BACKGROUND: Delta opioid receptor agonists mimic preconditioning (PC) in rat myocardium, corresponding to known cardiac delta opioid receptor expression in this species. METHODS: The messenger RNA transcript encoding the delta opioid receptor was identified in human atria and ventricles...

Myocardial reperfusion injury represents an important therapeutic target. The ability of several peptide growth factors, including transforming growth factor-beta1, insulin, insulin-like growth factor-1, cardiotrophin-1 and fibroblast growth factors, to modify reperfusion injury has been examined in recent studies. The protective effects of these agents may be related to the inhibition of apoptosis, especially during reperfusion, probably through p42/p44 MAP kinase and PI3-kinase/Akt signaling. Growth factor signaling may therefore represent a novel approach for the development of pharmacological strategies that attenuate reperfusion injury in the heart...